Stereoselective synthesis of the C94-C104 fragment of symbiodinolide

Article abstract of DOI:10.1016/j.tetlet.2012.06.005

Stereoselective synthesis of the C94-C104 fragment of symbiodinolide which is a polyol marine natural product with a molecular weight of 2860 has been accomplished. The synthetic route features Achmatowicz rearrangement and RuO₄-catalyzed dihydroxylation for the construction of the tetrahydropyran moiety and the dithiane addition to the aldehyde for the introduction of the side chain.

Full text of DOI:10.1016/j.tetlet.2012.06.005

Tetrahedron Letters 53 (2012) 4317–4319
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Stereoselective synthesis of the C94–C104 fragment of symbiodinolide
Hiroyoshi Takamura a, , Kosuke Tsuda a, Yohei Kawakubo a, Isao Kadota a, , Daisuke Uemura b
⇑
⇑
a Department of Chemistry, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushimanaka, Kita-ku, Okayama 700-8530, Japan
b Department of Chemistry, Faculty of Science, Kanagawa University, 2946 Tsuchiya, Hiratsuka 259-1293, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Stereoselective synthesis of the C94–C104 fragment of symbiodinolide which is a polyol marine natural
Received 19 April 2012
Revised 28 May 2012
Accepted 1 June 2012
Available online 13 June 2012
product with
a molecular weight of 2860 has been accomplished. The synthetic route features
Achmatowicz rearrangement and RuO4-catalyzed dihydroxylation for the construction of the tetrahydro-
pyran moiety and the dithiane addition to the aldehyde for the introduction of the side chain.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Polyol marine natural product
Symbiodinolide
Achmatowicz rearrangement
Dithiane addition
Symbiodinolide (1, Fig. 1) is a polyol marine natural product iso-
lated from dinoflagellate Symbiodinium sp.1 This molecule exhibits
voltage-dependent N-type Ca2+ channel-opening activity at 7 nM
and COX-1 inhibition activity at 2 lM. The planar structure of 1
was elucidated by the detailed 2D NMR analysis. However, the
huge and complex molecular structure of 1 featuring a molecular
weight of 2860 and the presence of 61 chiral centers has hampered
the complete stereochemical determination. Therefore, we are now
performing the chemical degradation of the natural product1,2 and
chemical synthesis of the fragments3 on 1 toward the complete
stereostructural elucidation. With regard to the C91–C99 carbon-
chain moiety, the stereochemical assignment was executed on
3
the basis of JH,H analysis and NOE correlations.1 Previously, we
synthesized the C79–C96 fragment by using spiroacetalization
and Kotsuki coupling as the key transformations.3a Herein, as a part
of our synthetic and structural studies of 1, we report the stereose-
lective synthetic route to the C94–C104 fragment.
Our retrosynthetic analysis of the C94–C104 fragment 2 is
outlined in Scheme 1. We envisaged that the carbon-framework
of 2 could be constructed through the coupling between dithiane
3 and aldehyde 4. The vicinal oxygen-functionalized moiety at
the C101 and C102 positions could be stereoselectively introduced
by dihydroxylation of enone 5. The carbon-skeleton of the methyl
acetal 5 could be constructed via Achmatowicz rearrangement4 of
optically pure alcohol 6, which could be prepared from commer-
cially available furfuryl alcohol.
Figure 1. Structure of symbiodinolide (1).
dimethylsilyl chloride (TBSCl)/imidazole gave TBS ether 7 in 96%
yield.5 Regioselective lithiation of the furan 7 with n-BuLi followed
by the addition of 2-benzyloxy acetaldehyde 86 provided racemic
alcohol 9. Albright–Goldman oxidation7 of 9 and subsequent asym-
metric transfer hydrogenation of the resulting furfuryl ketone with
HCO2H/Et3N in the presence of (S,S)-Noyori catalyst 10 (2 mol %)8
afforded the chiral alcohol 6 as a single stereoisomer, as judged
by the 400 MHz 1H NMR spectra of the corresponding MTPA esters.
Stereoselective construction of the tetrahydropyran part is
described in Scheme 2. Treatment of furfuryl alcohol with t-butyl-
⇑
Corresponding authors. Tel.: +81 86 251 7839; fax: +81 86 251 7836 (H.T.).
E-mail address: takamura@cc.okayama-u.ac.jp (H. Takamura).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.005

4318
H. Takamura et al. / Tetrahedron Letters 53 (2012) 4317–4319
H-99/H-101 and H-99/OCH3-103 of 12 confirmed that they were
in a syn relationship to each other. The small magnitude of
3J101,102 (3.6 Hz) indicated the syn correlation of these protons.
Although the detailed conformational analysis of 5 was not carried
out, the stereochemical outcome in the dihydroxylation can be
rationalized by the steric repulsion between the methoxy group
at the C103 position and the ruthenium reagent. After the vicinal
diol moiety of 12 was protected as an acetonide, reduction with
NaBH4 proceeded stereoselectively to provide axial alcohol 13.
The resulting configuration at the C100 position was determined
3
by the observed J99,100 (5.5 Hz). The alcohol 13 was transformed
into the corresponding S-methyl dithiocarbonate in 97% yield,
which was deoxygenated under Barton–McCombie conditions12
to afford tetrahydropyran 14 in 93% yield.
Next objective was to introduce the side chain, stereoselectively.
Removal of the benzyl protective group of 14 with LiDBB13 and
Scheme 1. Retrosynthetic analysis of the C94–C104 fragment 2.
subsequent Parikh–Doering oxidation14 gave the aldehyde
4
(Scheme 3). Deprotonation of the dithiane 315 with n-BuLi at room
temperature for 15 min, which were found to be the optimal condi-
tions by the deuterium exchange experiments, and subsequent
reaction of the resulting anion with the aldehyde 4 yielded alcohol
15 as a single stereoisomer.16 The stereoselectivity can be under-
stood by a Felkin–Anh model17 as illustrated in TS1. Treatment of
15 with Dess–Martin periodinane (DMP)18/pyridine afforded the
corresponding ketone in 95% yield, which was reduced with DI-
BAL-H to provide the desired alcohol 16 in quantitative yield. The
dithioacetal moiety of 16 was hydrolyzed with NCS/AgNO3 in aque-
The absolute configuration of the resulting asymmetric center was
confirmed by the modified Mosher method.9 Exposure of the alco-
hol 6 to the Achmatowicz conditions4 (NBS in THF/H2O) yielded
the desired rearrangement product 11 as a 1:1 diastereomeric mix-
ture, which was unstable, therefore, treated immediately with
(MeO)3CH in the presence of BF3ꢀOEt2 in Et2O at 0 °C to give the
methyl acetal 5 in 67% yield in two steps, along with its C103-epi-
mer (10% yield in two steps). Next, we examined the stereoselec-
tive dihydroxylation of the enone 5. When the enone 5 was
subjected to the OsO4-dihydroxylation conditions, the reaction
did not proceed at all. We speculated that this unfortunate phe-
nomenon resulted from the electron-deficient character of the
enone 5. Therefore, the dihydroxylation of 5 was carried out with
RuCl3/NaIO4 in the presence of ZnCl2 as a Lewis acid at 0 °C, which
are efficient conditions to the electron-deficient alkenes,10 to afford
the desired diol 12 in 73% yield as the sole product.11 The stereo-
chemistries at the C101 to C103 positions were verified by NOE
correlations and coupling constants. Thus, the observed NOEs of
ous CH3CN19 to afford
a-hydroxy ketone 17. Chelation-controlled
20
reduction of 17 with Zn(BH4)2 furnished the desired diol 2 as a
single stereoisomer.21 The absolute configuration at the C97 posi-
tion was confirmed by the modified Mosher method9 using the
mono-MTPA esters derived from 2.
In conclusion, we have synthesized the C94–C104 fragment 2 of
symbiodinolide (1) from furfuryl alcohol, which is the key synthetic
intermediate for the synthesis of the C79–C104 fragment. The syn-
thetic route features Achmatowicz rearrangement, RuO4-catalyzed
Scheme 2. Synthesis of 14.

H. Takamura et al. / Tetrahedron Letters 53 (2012) 4317–4319
4319
Scheme 3. Synthesis of 2.
7. Albright, J. D.; Goldman, L. J. Am. Chem. Soc. 1965, 87, 4214.
dihydroxylation, and coupling between the dithiane and the alde-
hyde. Further synthetic and structural studies on 1 are currently
underway and will be reported in due course.
8. (a) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc.
1996, 118, 2521; (b) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97.
9. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113,
4092.
10. Plietker, B.; Niggemann, M. J. Org. Chem. 2005, 70, 2402.
11. When the enone 5 was treated with RuCl3/NaIO4 in the presence of CeCl3 at
0 °C, the diol 12 was obtained in 51% yield.
12. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975, 1574.
13. (a) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 45, 1924; (b) Ireland, R.
E.; Smith, M. G. J. Am. Chem. Soc. 1988, 110, 854.
Acknowledgements
We appreciate the Kato Memorial Bioscience Foundation, The
Research Foundation for Pharmaceutical Sciences, The Society of
Synthetic Organic Chemistry, Japan (Shionogi Award in Synthetic
Organic Chemistry, Japan), and The Asahi Glass Foundation for their
financial supports. This research was supported by Grant-in-Aid for
Scientific Research from Japan Society for the Promotion of Science
(JSPS).
14. Parikh, J. R.; Doering, W. V. E. J. Am. Chem. Soc. 1967, 89, 5505.
15. The dithiane
3 was prepared from commercially available methyl (S)-3-
hydroxy-2-methylpropionate according to the known procedure. See: (a)
Walkup, R. D.; Boatman, P. D., Jr.; Kane, R. R.; Cunningham, R. T. Tetrahedron
Lett. 1991, 32, 3937; (b) Shotwell, J. B.; Roush, W. R. Org. Lett. 2004, 6, 3865.
16. The absolute stereochemistry at the C98 position of 15 was elucidated by
applying the modified Mosher method to the
a-hydroxy ketone which was
synthesized from 15 with NCS/AgNO3 in aqueous CH3CN.
17. For a selected review, see: Mengel, A.; Reiser, O. Chem. Rev. 1999, 99, 1191.
18. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155; (b) Dess, D. B.; Martin, J.
C. J. Am. Chem. Soc. 1991, 113, 7277.
19. (a) Corey, E. J.; Erickson, B. W. J. Org. Chem. 1971, 36, 3553; (b) Rao, A. V. R.;
Venkatswamy, G.; Javeed, S. M.; Deshpande, V. H.; Rao, B. R. J. Org. Chem. 1983,
48, 1552.
References and notes
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21. Diol 2: colorless oil; Rf = 0.40 (hexane/EtOAc=1:1); ½a D20
ꢂ10.2 (c 0.13, CHCl3);
ꢁ
IR (neat) 3437, 2927 cmꢂ1 1H NMR (400 MHz, CDCl3) d 7.21 (d, J = 8.3 Hz, 2H),
;
6.84 (d, J = 8.3 Hz, 2H), 4.43 (s, 2H), 4.37–4.31 (m, 1H), 4.01 (dt, J = 10.3, 3.0 Hz,
1H), 3.97 (d, J = 4.9 Hz, 1H), 3.81–3.78 (m, 1H), 3.78 (s, 3H), 3.73 (d, J = 10.7 Hz,
1H), 3.67 (d, J = 10.7 Hz, 1H), 3.62–3.58 (m, 1H), 3.41 (dd, J = 8.9, 4.3 Hz, 1H),
3.25–3.18 (m, 2H), 3.19 (s, 3H), 2.36–2.33 (m, 1H), 2.01–1.95 (m, 1H), 1.82–
1.73 (m, 3H), 1.47 (s, 3H), 1.42–1.36 (m, 1H), 1.29 (s, 3H), 0.92 (d, J = 6.8 Hz,
3H), 0.89 (s, 9H), 0.06 (s, 3H), 0.06 (s, 3H); 13C NMR (100 MHz, CDCl3) d 159.2,
129.6, 129.4, 113.8, 108.5, 99.9, 77.2, 76.4, 73.0, 72.1, 71.1, 71.1, 66.0, 60.3,
55.3, 47.9, 40.0, 32.2, 30.7, 29.8, 28.4, 26.5, 25.8, 18.4, ꢂ5.4, ꢂ5.5; HRMS (ESI-
TOF) calcd for C30H52O9SiNa (M+Na)+ 607.3278, found 607.3268.
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